The novel pyridone carboxylic acid compounds contained in an aqueous solution according to the present invention are described and claimed in pending U.S. patent application Ser. No. 08/160821 filed Dec. 3, 1993.
While a number of quinolone compounds such as Norfloxacin, Enoxacin, Ofloxacin, Ciprofloxacin and the like has been developed and proven successful in commerce owing to their potent and broad spectrum of antibacterial activities, much research has been conducted to increase the solubility of poorly soluble quinolone compounds in water. Many acids and bases which lead to the aqueous solution not only in which quinolone compounds were dissolved to the level that it may be suitable for injection or infusion but also whose shelf life is sufficiently long enough to fulfil the pharmaceutical requirements imposed on the injection and/or infusion.
Korean Patent Application Publication No. 87-1958 describes that the acids suitable for making the aqueous solutions of quinolone compounds include hydrochloric acid, methansulfonic acid, acetic acid, propionic acid, succinic acid and fumaric acid.
Korean Patent Application Publication No. 89-2040 describes examples of possible acids which do not lead to deposits of Norfloxacin and Enoxacin solutions, such as asparagine, glutamic acid and gluconic acid.
In Korean Patent Application Publication No. 89-2240, sodium hydroxide, potasium hydroxide, ethanolamine, lysine, N-methylglutamine and arginine are disclosed as examples of bases which do not lead to deposits in aqueous solutions of quinolone medicaments. However, the aqueous solution of quinolone compounds which is prepared using such bases as solubilizing agents is unsuitable or poorly very suitable for injection and/or infusion because the pH of the solution is too high.
U.S. Pat. No. 4,705,789 relates to solutions characterized by containing lactic acid salts of piperazinylquinolone- and piperazinylazaquinolone-carboxylic acids and at least one acid which does not lead to precipitates, in particular lactic acid.
U.S. Pat. No. 4,957,922 relates to aqueous infusion solutions comprising 1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-7-(1-piperazinyl)-quinoline-3-ca rboxylic acid (=ciprofloxacin) and an amount of at least one physiologically tolerated acid which suffices to dissolve the active compound.
As the novel pyridone carboxylic acid compounds of formula I as represented below were in vitro evaluated about their efficacy, it was found that these compounds, especially 1-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-([1.alpha., 5.alpha.,6.beta.]6-amino-1-methyl-3-azabicyclo[3.2.0]heptan-3-yl)-1,8-naph tyridine-3-carboxylic acid(hereinafter "compound A") exhibit superior antibacterial activities to Lomefloxacin and Ofloxacin which are utilized for combating gram-negative and gram-positive bacteria and that these compounds including compound A has 2 to 16 times as much antibacterial activity as Ciprofloxacin, especially against gram-positive bacteria. Moreover, the novel pyridone carboxylic acid compounds, especially compound A show better bioavailability and half-life than drugs of quinolone compounds which either are commercially available or still on developments.
However, The novel pyridone carboxylic acid compounds including compound A as represented below have some difficulties in being formulated into aqueous solutions for injection and/or infusion, since it is not substantially soluble or little soluble in water as most known qunolone compounds having antibacterial activities are.
It was very suprising to find that by addition of hydrochloric acid, gluconic acid lactone, gluconic acid, malic acid, succinic acid, aspattic acid or mixtures thereof, it was possible to form injection and/or infusion solutions not only having higher amounts of the compounds of the formula I dissolved in water but also having appropriate pH and stability for the pharmaceutical requirements to be imposed on such solutions. Moreover, it was suprisingly found that when the combinations of at least one of the compounds of the formula I with the said acids were formulated into injection and/or infusion solutions, not only does the pH of the solutions maintain in the appropriate range for the administration but also no deposits form during storage in a long period.
Therefore, the object of the present invention is to provide aqueous solutions in which effective amounts of the compounds of the formula I as represented below were dissolved so as to be used as injection and/or infusion solutions.